The 9-valent HPV vaccine has the potential to prevent ~90% cervical cancers. An innovative regulatory approach was taken to accelerate development.
(1)An adaptive, seamless phase IIB/III design was used to proceed from dose selection (phase IIB) to phase III without pause to shorten the development time
(2)A hybrid approach was taken to define the primary endpoints.
i.An active comparator (Gardasil) had to be used.
ii.Since HPV vaccines are highly efficacious, few HPV6/11/16/18-related disease endpoints were expected, precluding a comparison based on efficacy.
iii.Efficacy for HPV6/11/16/18 was inferred based on non-inferior immunogenicity given the absence of immune correlate of protection
iv.Efficacy for the new HPV types was established based on efficacy endpoints
v.A hybrid approach for the primary endpoints facilitated the implementation of the seamless design.
Adaptive design with hybrid approach for primary endpoints is novel for vaccine development. Careful planning and rigorous execution of the Phase IIB/III adaptive design and dialogue with regulators was critical to success.
The 9-valent HPV vaccine was licensed as Gardasil 9 in the US in Dec 2014, Canada in Feb 2015 and EU and Australia in Jun 2015. A case study of this approach is presented.
This regulatory approach shortened development time, reduced the number of subjects in trials and offers an innovative approach to vaccine development.